METHODS FOR TREATING CANCER USING A COMBINATION OF A PD-1 ANTAGONIST, A CTLA4 ANTAGONIST, AND LENVATINIB OR A PHARMACEUTICALLY ACCPETABLE SALT THEREOF
20230118596 · 2023-04-20
Assignee
- Merck Sharp & Dohme LLC (Rahway, NJ, US)
- Eisai R&D Management Co., Ltd. (Bunkyo-ku, Tokyo, JP)
Inventors
- Blanca Homet Moreno (Philadelphia, PA, US)
- Nageatte Ibrahim (Plymouth Meeting, PA, US)
- Rodolfo Fleury Perini (Wynnewood, PA, US)
- Scott J. Diede (New Hope, PA, US)
- Scot W. Ebbinghaus (Lansdale, PA, US)
- Rachel Allison Altura (Westerly, RI, US)
Cpc classification
A61K39/3955
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K2039/545
HUMAN NECESSITIES
A61K2039/507
HUMAN NECESSITIES
A61K39/3955
HUMAN NECESSITIES
C07D215/233
CHEMISTRY; METALLURGY
International classification
C07K16/28
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
Abstract
Provided herein are methods of treating cancer (e.g., melanoma or RCC), which comprise administering to a human patient in need thereof: (a) a PD-1 antagonist; (b) a CTLA4 antagonist; and (c) lenvatinib represented by Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are kits containing such agents and uses of therapeutic combinations of such agents for the treatment of cancer.
##STR00001##
Claims
1. A method of treating cancer, comprising administering to a human patient in need thereof: (a) a PD-1 antagonist; (b) a CTLA-4 antagonist; and (c) 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (lenvatinib) or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer, colorectal cancer, renal cell carcinoma (RCC), hepatocellular carcinoma, and melanoma.
3. The method of claim 2, wherein the cancer is advanced RCC or metastatic RCC.
4-5. (canceled)
6. The method of claim 2, wherein the cancer is advanced melanoma or metastatic melanoma.
7-8. (canceled)
9. A kit comprising: (a) a PD-1 antagonist; (b) a CTLA-4 antagonist; and (c) 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (lenvatinib) or a pharmaceutically acceptable salt thereof.
10-16. (canceled)
17. The method of claim 1, wherein the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen binding fragment thereof.
18-20. (canceled)
21. The method of claim 1, wherein the CTLA-4 antagonist is an anti-human CTLA4 monoclonal antibody or antigen binding fragment thereof.
22-23. (canceled)
24. The method of claim 17, wherein the anti-human PD-1 monoclonal antibody is pembrolizumab.
25. The method of claim 17, wherein the anti-human PD-1 monoclonal antibody is nivolumab or cemiplimab.
26. (canceled)
27. The method of claim 21, wherein the anti-human CTLA-4 monoclonal antibody comprises a V.sub.L CDR1, a V.sub.L CDR2, and a V.sub.L CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a V.sub.H CDR1, a V.sub.H CDR2, and a V.sub.H CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 1, 2, and 3, respectively.
28. The method of claim 21, wherein the anti-human CTLA-4 monoclonal antibody comprises a V.sub.L region comprising an amino acid sequence as set forth in SEQ ID NO:14, and a V.sub.H region comprising an amino acid sequence as set forth in SEQ ID NO:15.
29. The method of claim 21, wherein the anti-human CTLA-4 monoclonal antibody comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 23 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:22.
30. The method, of claim 1, wherein: (a) the PD-1 antagonist is pembrolizumab; and (b) the CTLA-4 antagonist is a monoclonal antibody or antigen binding fragment thereof comprising a V.sub.L CDR1, a V.sub.L CDR2, and a V.sub.L CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a V.sub.H CDR1, a V.sub.H CDR2, and a V.sub.H CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 1, 2, and 3, respectively.
31. The method of claim 1, wherein: (a) the PD-1 antagonist is nivolumab or cemiplimab; and (b) the CTLA-4 antagonist is a monoclonal antibody or antigen binding fragment thereof comprising a V.sub.L CDR1, a V.sub.L CDR2, and a V.sub.L CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a V.sub.H CDR1, a V.sub.H CDR2, and a V.sub.H CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 1, 2, and 3, respectively.
32. (canceled)
33. The method of claim 30 wherein the human patient is administered 200 mg, 240 mg, 400 mg, or 2 mg/kg pembrolizumab, and wherein pembrolizumab is administered once every six weeks.
34. The method of claim 30, wherein the human patient is administered 400 mg pembrolizumab, and wherein pembrolizumab is administered once every six weeks.
35. The method of claim 31, wherein the human patient is administered 240 mg or 3 mg/kg nivolumab once every two weeks, 480 mg nivolumab once every four weeks, or 350 mg cemiplimab once every three weeks.
36. (canceled)
37. The method of claim 33, wherein the human patient is administered from about 1 mg to about 200 mg of the anti-human CTLA-4 antibody, and wherein the anti-human CTLA4 antibody is administered once every six weeks.
38. (canceled)
39. The method of claim 33, wherein the human patient is administered 25 mg of the anti-human CTLA-4 antibody, and wherein the anti-human CTLA4 antibody is administered once every six weeks.
40. The method of claim 33, wherein the human patient is administered 8, 10, 12, 14, 18, 20, or 24 mg lenvatinib or a pharmaceutically acceptable salt thereof, and wherein lenvatinib or the pharmaceutically acceptable salt thereof is administered once daily.
41. A method of treating melanoma, comprising administering to a human patient in need thereof: (a) 400 mg pembrolizumab; (b) 25 mg of an anti-human CTLA-4 monoclonal antibody or antigen binding fragment thereof that comprises a V.sub.L CDR1, a V.sub.L CDR2, and a V.sub.L CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a V.sub.H CDR1, a V.sub.H CDR2, and a V.sub.H CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 1, 2, and 3, respectively; and (c) 20 mg lenvatinib.
42. The method of claim 41, wherein each of (a) and (b) is administered once every six weeks, and wherein (c) is administered once daily.
43. (canceled)
44. The method of claim 41, wherein (a) and (b) are administered on the same day, and wherein (a) and (b) are administered sequentially or concurrently.
45. The method of claim 1, wherein the pharmaceutically acceptable salt thereof is lenvatinib mesylate.
Description
EXAMPLES
[0546] The examples in this section are offered by way of illustration, and not by way of limitation.
Example 1: Clinical Trial of Administering an Anti-PD-1 Antibody in Combination with an Anti-CTLA4 Antibody, and Lenvatinib in Melanoma Patients
[0547] The design overview for the Phase 1/2 open-label rolling arm umbrella platform design of a CTLA4 antagonist (MK-1308) in combination with pembrolizumab and lenvatinib in patients with Melanoma. Participants with Melanoma undergo ICF screening (no molecular testing required), and proceed to substudy 02A where participants have PD-1 refractory melanoma.
[0548] This study is a phase 1/2, rolling arm, multicenter, open-label, adaptive design study that will evaluate within this study the efficacy of investigational agents for the treatment of PD-1 refractory melanoma.
[0549] Participants will be administered 400 mg Pembrolizumab once every six weeks (Q6W) by IV in combination with a CTLA4 antagonist (MK-1308) (at a fixed dose of 25 mg Q6W), and lenvatinib (20 mg QD (once daily) PO (by mouth, orally)). Lenvatinib is administered at the dose specified orally every day. When more than 1 agent is to be given on the same day, the order of administration is pembrolizumab and then lenvatinib.
[0550] At the time of the Oct. 28, 2020 data cutoff, a total of 14 participants were enrolled in the triplet combination of pembrolizumab (400 mg) Q6W, MK-1308 (25 mg) Q6W, and Lenvatinib (20 mg) QD. 10 of these participants were enrolled in the Safety Lead-in phase and 4 of these participants were enrolled in the Efficacy phase. 7 of the participants in the safety lead-in phase completed DLT monitoring window. All 14 participants were analyzed. There were no dose limiting toxicities (DLT's) in the Safety Lead-in phase, and we were able to establish recommended phase 2 dosing at the 20 mg Lenvatinib dose. This triplet combination with lenvatinib at 20 mg has been generally well tolerated. 4 patients (28.6%) experienced grade 3-5 drug related AE's, all grade 3, and there were 2 SAE's. 2 of the 4 patients (14.3%) that experienced grade 3-5 drug-related AE's experienced hypertension, 1 patient (7.1%) experienced increased blood alkaline phosphatase, one patient (7.1%) experienced an embolism, and 1 patient (7.1%) experienced increased gamma-glutamyltransferase.
[0551] Out of the 14 study participants, 4 patients experienced Grade 3 drug-related adverse events, no Grade 4 and 5 drug-related adverse events have been observed. 2 participants had adverse events of special interest (AEOSI). One participant had hypothyroidism and one participant had pancreatitis. Out of the total 14 treated participants, preliminary data shows that 8 (57.1%) had one or more drug-related AE's.
[0552] Two patients have reduced their doses of Lenvatinib, one discontinued Lenvatinib completely due to toxicities—Participant continued treatment with MK1308+ pembrolizumab. One death was reported in this triplet combination efficacy phase after the data cutoff.
[0553] There are 3 predetermined dose levels of lenvatinib that may be explored (Dose Level 0, Dose Level −1, Dose Level −2).
[0554] Patient characteristics are found in Table 4. Additional patient data from the Safety Lead-in phase can be found in the following tables.
TABLE-US-00004 TABLE 4 Participant Characteristics (APaT Population) by Treatment Arm MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD n (%) Participants in population 14 Sex Male 12 85.7 Female 2 14.3 Age (Years) <65 8 57.1 ≥65 6 42.9 Range 33 to 78 Race White 12 85.7 Missing 2 14.3 Ethnicity Hispanic or Latino 1 7.1 Not Hispanic Or Latino 12 85.7 Not Reported 1 7.1 ECOG 0 8 57.1 1 6 42.9 LDH ≤ULN 12 85.7 >ULN but <2X ULN 1 7.1 ≥2X ULN 1 7.1 Overall Cancer Stage at Enrollment IIIC 2 14.3 IV 12 85.7 Brain Metastasis* No 14 100.0 Metastatic Staging MO 2 14.3 M1a(0) 4 28.6 M1b(0) 1 7.1 M1c(0) 5 35.7 M1c(1) 2 14.3 Baseline Tumor Size (mm) based on Central Evaluation Participants with Data 7 Median 20 Range 10.0 to 31.0 Prior Lines of Therapy One Line 11 78.6 Two Lines 3 21.4 Prior Adjuvant Systemic Immunotherapy Yes 12 85.7 No 2 14.3 Prior Systemic Immunotherapy for Progressive/Relapsed Disease Yes 2 14.3 No 12 85.7 Prior Adjuvant Systemic BRAF/MEK Inhibitor Yes 1 7.1 No 13 92.9 Prior Systemic BRAF/MEK inhibitor for Progressive/Relapsed Disease Yes 1 7.1 No 13 92.9 BRAF Mutation Status BRAF mutant 5 35.7 BRAF wild type 9 64.3 BRAF Status and Prior BRAFi/MEKi treatment use BRAF mutant (no prior treatment) 3 21.4 BRAF mutant, prior adjuvant BRAFi/MEKi 1 7.1 treatment, no BRAFi/MEKi treatment for metastatic disease BRAF mutant, prior BRAFi/MEKi treatment 1 7.1 for metastatic disease, no adjuvant BRAFi/ MEKi treatment No participants with M stage M1d; no participants had received previous localized treatment for brain metastasis
TABLE-US-00005 TABLE 5 Participants With Clinically Significant Adverse Events by Lenvatinib CSAE Category and Preferred Term (Incidence > 0%) (APaT Population) n % Participants in population 14 with one or more adverse events 8 (57.1) with no adverse events 6 (42.9) Cardiac Dysfunction 1 (7.1) Cardiac failure 1 (7.1) Hemorrhage 1 (7.1) Haemoptysis 1 (7.1) Hepatotoxicity 1 (7.1) Gamma-glutamyltransferase increased 1 (7.1) Hypertension 6 (42.9) Hypothyroidism 2 (14.3) Blood thyroid stimulating hormone increased 1 (7.1) Hypothyroidism 1 (7.1) Proteinuria 1 (7.1) Renal Events 1 (7.1) Blood creatinine increased 1 (7.1)
TABLE-US-00006 TABLE 6 Summary of Participants with Drug related Adverse Events MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD n (%) Subjects in APaT population 14 100 With drug-related AE 12 85.7 With Grade 3-5 drug-related AE 4 28.6 With dose interruptions due to drug-related 3 21.4 AE With drug-related SAE 2 14.3 Who discontinued one or more drugs due 1* 7.1 to a drug-related AE Who died due to a drug-related\AE 0 0 Who discontinued all study treatment due 0 0 to a drug-related AE *Lenvatinib was discontinued after C3 due to drug related G3 embolism. Participant continued treatment with MK1308+ pembrolizumab {circumflex over ( )}Details in slides 22 to 24 (pembrolizumab 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD)
TABLE-US-00007 TABLE 7 Particants With Serious Adverse Events (Incidence > 0%) By Decreasing Frequence of Preffered Term (APaT Population) MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD n (%) Participants in population 14 With one or more adverse events 2 (14.3) With no adverse events 12 (85.7) Embolism 1 (7.1) Pancreatitis 1 (7.1) Every participant is counted a single time for each applicable row and column. MedDRA V23.1 preferred terms “Neoplasm progression”, “Malignant neoplasm progression” and “Disease progression” not related to the drug are excluded. Serious advese events up to 120 days of last dose are included. Database Cutoff Date: 28 Oct. 2020.
TABLE-US-00008 TABLE 8 Participants with Grade 3-5 Adverse Events (Incidence > 0%) by Decreasing Frequence of Preferred Term (APaT Population) MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD n (%) Participants in population 14 With one or more adverse events 4 (28.6) With no adverse events 10 (71.4) Hypertension 2 (14.3) Blood alkaline phosphatase increased 1 (7.1) Embolism 1 (7.1) Gamma-glutamyltransferase increased 1 (7.1) Every participant is counted a single time for each applicable row and column. MedDRA V23.1 preferred terms “Neoplasm progression”, “Malignant neoplasm progression” and “Disease progression” not related to the drug are excluded. Non-serious advese events up to 90 days of last dose and serious adverse events up to 120 days of last dose are included. Grades are based on NCI CTCAE version 5. Database Cutoff Date: 28 Oct. 2020.
TABLE-US-00009 TABLE 9 Adverse Event Summary (APaT Population) MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD N (%) Participants in population 14 With one or more adverse events 12 (85.7) With no adverse event 2 (14.3) With drug-related.sup.a adverse events 12 (85.7) related to Pembrolizumab 10 (71.4) related to Quavonlimab 10 (71.4) related to Lenvatinib 12 (85.7) With toxicity grade 3-5 adverse events 4 (28.6) With toxicity grade 3-5 drug-related adverse events 4 (28.6) With serious adverse events 2 (14.3) With serious drug-related adverse events 2 (14.3) Who died 0 (0.0) Who died due to a drug-related adverse event 0 (0.0) With dose interruption.sup.b due to an adverse event 3 (21.4) interruption of Pembrolizumab 0 (0.0) interruption of Quavonlimab 0 (0.0) interruption of Lenvatinib 3 (21.4) With dose reduction of Lenvatinib due to an adverse event 0 (0.0) Discontinued.sup.c due to an adverse event 1 (7.1) discontinued Pembrolizumab 0 (0.0) discontinued Quavonlimab 0 (0.0) discontinued Lenvatinib 1 (7.1) Discontinued due to a drug-related adverse event 1 (7.1) Discontinued due to a serious adverse event 1 (7.1) Discontinued due to a serious drug-related adverse event 1 (7.1) .sup.aDetermined by the investigator to be related to the drug. .sup.bDose interrption of any study medication .sup.cStudy medication withdrawn of any study medication. Non-serious adverse events up to 90 days following the last dose and serious adverse events up to 120 days followign the last dose are included. MedDRA V23.1 preferred terms “Neoplasm progression”, “Malignant neoplasm progression” and “Disease progression” not related to the drug are excluded. (Database cutoff Date: 28 Oct. 2020).
TABLE-US-00010 TABLE 10 Summary of Drug Exposure (APaT Population) MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD (N = 14) Number Days on Levantinib Mean 31.8 Median 21.5 SD 26.50 Range 1.0 to 90.0 Number Days on Pembrolizumab Mean 24.9 Median 1.0 SD 31.60 Range 1.0 to 85.0 Number Days on Quavonlimab Mean 24.9 Median 1.0 SD 31.60 Range 1.0 to 85.0 Number of Adminstration of Lenvatinib Mean 2.1 Median 1.5 SD 1.27 Range 1.0 to 5.0
TABLE-US-00011 TABLE 11 Participants with Adverse Events by System Organ Class and Preferred Term (Incidence > 0%) (APaT Population) MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD n (%) Participants in population 14 With one or more adverse events 12 (85.7) With no adverse events 2 (14.3) Blood and lymphatic system disorders 2 (14.3) Lymphopenia 1 (7.1) Neutropenia 1 (7.1) Thrombocytopenia 1 (7.1) Cardiac disorders 1 (7.1) Cardiac failure 1 (7.1) Endocrine disorders 1 (7.1) Hypothyroidism 1 (7.1) Gastrointestinal disorders 6 (42.9) Abdominal pain 1 (7.1) Abdominal pain upper 1 (7.1) Constipation 2 (14.3) Diarrhoea 2 (14.3) Dry Mouth 1 (7.1) Dyspepsia 1 (7.1) Lip discolouration 1 (7.1) Odnophagia 1 (7.1) Pancreatitis 1 (7.1) Stomatitis 1 (7.1) General disorders and adminsitration 6 (42.9) site conditions Asthenia 3 (21.4) Chest discomfort 1 (7.1) Chest pain 1 (7.1) Chills 1 (7.1) Fatigue 1 (7.1) Hyperthermia 1 (7.1) Mucosal inflammation 2 (14.3)
TABLE-US-00012 TABLE 12 Participants with Adverse Events by System Organ Class and Preferred Term (Incidence > 0%) (APaT Population) MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD n (%) General Disorders and Administration 6 (42.9) Site Conditions Pyrexia 2 (14.3) Infections and infestations 2 (14.3) Candida infection 1 (7.1) Folliculitis 2 (14.3) Injury, poisoning and procedural 1 (7.1) complications Arthropod bite 1 (7.1) Wound complication 1 (7.1) Investigations 4 (28.6) Blood alkaline phosphatase increased 1 (7.1) Blood creatinine increased 1 (7.1) Blood lactate dehydrogenase 1 (7.1) Blood lactic acid increased 1 (7.1) Blood thyroid stimulating hormone 1 (7.1) increased Blood triglycerides increased 1 (7.1) C-reactive protein increased 1 (7.1) Gamma-glutamyltransferase increased 1 (7.1) Lipase increased 2 (14.3) Weight decreased 2 (14.3) Metabolism and nutrition disorders 4 (28.6) Decreased appetite 2 (14.3) Folate deficiency 1 (7.1) Hypervolaemia 1 (7.1) Hypoalbuminaemia 1 (7.1) Hypokalaemia 1 (7.1) Hypomagnesaemia 2 (14.3) Hypophosphataemia 2 (14.3) Musculoskeletal and connective tissue 3 (21.4) disorders Arthralgia 1 (7.1) Back Pain 1 (7.1)
TABLE-US-00013 TABLE 13 Particpants with Adverse Events by System Organ Class and Preferred Term (Incidence > 0%) (APaT Population) MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD n (%) Musculoskeletal and connective tissue 3 (21.4) disorders Myalgia 1 (7.1) Neoplasms benign, malignant and 1 (7.1) unspecified (incl cysts and polps) Tumor pain 1 (7.1) Nervous System Disorders 4 Headache 3 (21.4) Sciatica 1 (7.1) Renal and Urinary Disorders 1 (7.1) Proteinuria 1 (7.1) Respiratory, thoracic and mediastinal 7 (50.0) disorders Cough 1 (7.1) Dysphonia 6 (42.9) Dyspnoea exertional 1 (7.1) Haemoptysis 1 (7.1) Oropharyngeal pain 1 (7.1) Painful respiration 1 (7.1) Productive cough 1 (7.1) Skin and subcutaneous tissue disorders 4 (28.6) Night sweats 1 (7.1) Pruritius 1 (7.1) Rash 1 (7.1) Urticaria 1 (7.1) Vascular Disorders 8 (57.1) Deep vein htrombosis 1 (7.1) Embolism 1 (7.1) Hypertension 6 (42.9)
TABLE-US-00014 TABLE 14 Participants with Adverse Events by System Organ Class and Preferred Term (Incidence > 0%) (APaT Population) MK-3475 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD (N = 14) n (%) Vascular Disorders 8 (57.1) Hypotension 1 (7.1) Every participant is counted a single time for each applicable row and column Non-serious adverse events up to 90 days of last dose and serious adverse events up to 120 days of last dose are included. MedDRA V23.1 preferred terms “Neoplasm progression”, “Malignant neoplasm progression” and “Disease progression” not related to the drug are excluded. Database Cutoff Date: 28 Oct. 2020
TABLE-US-00015 TABLE 15 Participants With Adverse Events Clinically Significant Adverse Events (CSAE) by Maximum Toxicity Grade pembrolizumab 400 mg Q6W + MK-1308 25 mg Q6W + Lenvatinib 20 mg QD n (%) Participants in population 14 with one or more Adverse Events 8 57.1 Grade 1 1 7.1 Grade 2 4 28.6 Grade 3 2 14.3 Grade 4 1 7.1 with no Adverse Events 6 42.9 Hypothyroidism 1 7.1 Grade 2 1 7.1 Blood creatinine increased 1 7.1 Grade 2 1 7.1 Blood thyroid stimulating hormone 1 7.1 increased Grade 1 1 7.1 Cardiac failure 1 7.1 Grade 1 1 7.1 Gamma-glutamyltransferase increased 1 7.1 Grade 4 1 7.1 Haemoptysis 1 7.1 Grade 1 1 7.1 Hypertension 6 42.9 Grade 2 4 28.6 Grade 3 2 14.3 Proteinuria 1 7.1 Grade 2 1 7.1
Objectives and Endpoints
[0555] A listing of objectives and endpoints for the clinical trial substudy are shown in the table below.
TABLE-US-00016 TABLE 16 Objectives and Endpoints Objectives Endpoints Primary Safety Lead-in Phase: To assess the safety and Dose-limiting toxicity (DLTs). tolerability, and to establish an RP2D if applicable, Adverse Events (AEs). of treatment combinations that have not been Study intervention discontinuations due evaluated in a previous Phase 1 study. to AEs. Efficacy Phase: To assess the safety and tolerability Adverse Events (AEs). of each treatment arm based on the proportion of Study intervention discontinuations due participants with adverse events (AEs). to AEs. Efficacy Phase: To evaluate objective response rate Objective Response (OR): Complete (ORR) of each treatment arm as assessed by response (CR) or partial response (PR). Blinded Independent Central Review (BICR) per RECIST 1.1. Secondary Efficacy Phase: To evaluate the duration of response DOR: For participants who demonstrate (DOR) as assessed by BICR per RECIST 1.1. CR or PR, DOR is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. Efficacy Phase: To evaluate progression-free PFS: The time from the date of survival (PFS) as assessed by BICR per randomization to the date of the first RECIST 1.1. documented PD per RECIST 1.1 by BICR, or death from any cause, whichever occurs first. Efficacy Phase: To evaluate overall survival (OS) OS: The time from the date of randomization to the date of death. Efficacy Phase: To evaluate clinical benefit rate CBR: The percentage of participants who (CBR) per RECIST 1.1 as assessed by BICR have achieved stable disease (SD) ≥6 months or CR or PR based on assessments by BICR per RECIST 1.1. Tertiary/Exploratory Efficacy Phase: To evaluate the correlation of tumor Tumor Size Change: Percent change of size change with DOR, PFS, and OS. the sum of target lesions from baseline Efficacy Phase: To characterize the pharmacokinetic Plasma concentration of each agent (PK) profiles and anti-drug antibody (ADA) ADA formation rate formation for investigational agents. Efficacy Phase: To identify molecular (genomic, Molecular (genomic, metabolic, and/or metabolic, and/or proteomic) biomarkers that may proteomic) determinants of response or be indicative of clinical response/resistance, safety, resistance to treatments, using blood and/or the mechanism of action of study treatment and/or tumor tissue. combinations with pembrolizumab, lenvatinib and other investigational agents.
Dosing
[0556] Initially, 3 Dose-Limiting Toxicity (DLT) evaluable participants will be enrolled in Dose Level 0. More than 3 to 6 participants may be enrolled to Dose Level 0 if needed to replace participants who are not evaluable for DLT or to ensure a thorough evaluation of the dose level during the Safety Lead-In Phase. An event will be considered a DLT if it occurs during the first treatment cycle, or 3 weeks from the first dose of study intervention and meets at least 1 of the criteria. Patients who experience a DLT will be allowed to remain on the substudy if they meet the following criteria: (1) the investigator believes it is appropriate for participant to remain on the substudy, and (2) the event has resolved and no longer meets the definition of DLT.
[0557] Dose recommendations for the next evaluable participants will depend on the observed number of DLTs in the first 3 DLT evaluable participants and the mTPI table until 10 participants are studied at Dose Level 0 with ≤4 of 10 participants experiencing a DLT. In the event Dose Level 0 is not tolerable, lower dose levels may be selected. As participants become evaluable for DLT assessment, the number of participants who are evaluable for DLT versus the number of participants who developed a DLT will be continuously assessed.
[0558] If enrollment expands to 10 participants for a dose level, and ≤4 of the 10 participants develop a DLT, then the dose confirmation will stop. If enrollment expands to 10 participants for a dose level and >4/10 participants develop a DLT, then the next lower dose may be expanded to further explore the dose-response relationship.
[0559] The investigator may attribute each toxicity event to lenvatinib alone, to the CTLA4 antagonist (ex. MK-1308) alone, to pembrolizumab alone, or to the combination, and follow the dose delay and restart criteria for the CTLA4 antagonist (ex. MK-1308) and pembrolizumab and for lenvatinib. Participants may not have any dose modifications of the CTLA4 antagonist (ex. MK-1308) or pembrolizumab in this investigational treatment arm. If toxicity attributed to the CTLA4 antagonist (ex. MK-1308) or pembrolizumab does not resolve or the criteria for resuming treatment are not met, the participant must be discontinued from the CTLA4 antagonist (ex. MK-1308) or pembrolizumab. Participants may have dose modifications of lenvatinib in this investigational treatment arm. If toxicity attributed to lenvatinib does not resolve or the criteria for resuming treatment are not met, the participant must be discontinued from lenvatinib. Refer to Dosing Tables below (Tables 6-9).
[0560] Holding of 1 agent and not the other agent is appropriate if, in the opinion of the investigator, the toxicity is clearly related to 1 of the study interventions. For example, in the combination arm, if the CTLA4 antagonist (ex. MK-1308) or pembrolizumab is held due to an adverse event attributed to that drug, lenvatinib may continue to be administered. Appropriate documentation is required regarding which drug the investigator is attributing to the adverse event. If, in the opinion of the investigator, the toxicity is related to the combination of 2 agents, then both drugs should be held according to recommended dose modifications. Exceptional circumstances to following the dose modification table may be considered after consultation with the Sponsor.
[0561] In case toxicity does not resolve to Grade 0 to 1 within 12 weeks after last treatment, the CTLA4 antagonist (ex. MK-1308) and/or pembrolizumab and/or lenvatinib should be discontinued after consultation with the Sponsor.
[0562] With investigator and Sponsor agreement, participants with a laboratory AE still at Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and controlled.
[0563] After any Grade 4 drug-related AE, participants should not restart study intervention without consultation with the Sponsor. (Toxicity must have resolved to Grade 0 to 1 or baseline prior to restarting).
TABLE-US-00017 TABLE 17 Dosing Levels of Pembrolizumab, the CTLA4 antagonist (ex. MK-1308), and Lenvatinib Dose Level 0 Dose Level −1 Dose Level −2 Pembrolizumab 400 mg 400 mg 400 mg anti-CTLA4 antibody 25 mg 25 mg 25 mg Lenvatinib 20 mg 14 mg 10 mg
TABLE-US-00018 TABLE 18 Dose Modifications Guidelines for Lenvatinib-Related Adverse Events Treatment-Related Toxicity.sup.a, b Management Dose Adjustment Grade 1 or Tolerable Grade 2 Continue treatment No change Intolerable Grade 2.sup.c, d, or Grade 3.sup.e, g First Occurrence Interrupt lenvatinib until Reduce lenvatinib dose resolved to Grade 0-1, or to 14 mg once a day tolerable Grade 2 (1-level reduction) Second Occurrence Interrupt lenvatinib until Reduce lenvatinib dose (same toxicity or resolved to Grade 0-1, or to 10 mg once a day new toxicity) tolerable Grade 2 (1-level reduction) Third Occurrence Interrupt lenvatinib until Reduce lenvatinib dose (same toxicity or resolved to Grade 0-1, or to 8 mg once a day new toxicity) tolerable Grade 2 (1-level reduction) Fourth Occurrence Interrupt lenvatinib Discuss with sponsor (same toxicity or new toxicity) Grade 4f: Discontinue Study Intervention .sup.aAn interruption of study intervention with lenvatinib for more than 28 days will require Sponsor approval before study intervention can be resumed. .sup.bInitiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or diarrhea prior to any lenvatinib interruption or dose reduction. .sup.cApplicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable. .sup.dObese participants (BMI ≥ 30) with weight loss do not need to return to their baseline weight or within 10% of their baseline weight (ie, Grade 1 weight loss). These participants may restart study intervention at a lower dose once their weight remains stable for at least 1 week and they reach at least a BMI of 25. The new stable weight should be used as the new baseline for further dose reductions. For asymptomatic laboratory abnormalities, such as Grade ≥ 3 elevantions of amylase and lipase that are not considered clinically relevant by the investigator, continuation of treatment should be discussed with sponsor. fExcluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. .sup.gFor Grade 3 thromboembolic event, permanently discontinue lenvatinib.
TABLE-US-00019 TABLE 19 Dose Modification and Toxicity Management Guidelines for Immune- Related Adverse Events Associated with Pembrolizumab Toxicity grade Action with Corticosteroid and/ Monitoring irAEs (CTCAE V5.0) Pembrolizumab or other therapies and follow-up Pneumonitis Grade 2 Withold Adminster corticosteroids Monitor participants Recurrent Permanently (initial dose of 1-2 mg/lg for signs and symptons of Grade 2, discontinue prednisone or equivalent pneumonitis. Evaluate Grade 3, followed by taper) participants with suspected or 4 Add prophylactic antibiotics pneumonitis with radiographic for opportunistic infections imaging and initiate corticosteriod treatment. Diarrhea/ Grade 2 or 3 Withold Adminster corticosteroids Monitor participants for Colitis Recurrent Permanently (initial dose of 1-2 mg/lg signs andsymptons of Grade 3 or discontinue prednisone or equivalent enterocolitis (ie, diarrhea, Grade 4 followed by taper) abdominal pain, blood or mucus in stool with or without fever) and of bowel perforation (eg, peritoneat signs and ileus) General Instructions: 1. Severe and life-threatening irAEs shoud be treated with IV cortiscosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment. 3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
TABLE-US-00020 TABLE 20 Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines Premedication at NCI CTCAE Grade Treatment Subsequent Dosing Grade 1 Increase monitoring of vital signs as None Mild reaction; medically indicated until the participant is infusion interruption deemed medically stable in the opinion of not indicated; the investigator. intervention not indicated. Grade 2 Stop Infusion Participants may be Requires therapy or Additional appropriate medical therapy may premedicated 1.5 hours infusion interruption include but is not limited to: (±30 minutes) prior to but responds promptly IV fluids, Antihistamines, NSAIDs, infusion of pembrolizumab to symptomatic treatment Acetaminophen, Narcotics. with: (eg, antihistamines, Increase monitoring of vital signs as Diphenhydramine 50 mg NSAIDs, narcotics, medically stable in the opinion of the PO (or equivalent dose IV fluids); prophylactic investigator. of antihistamine). medications indicated If symptons resolve within 1 hour of Acetaminophen 500-1000 mg for ≤24 hours. stopping drug infusion, the infusion may be PO (or equivalent dose of restarted at 50% of the original infusion rate analgesic). (eg, from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until symptons resolve and the participant should be premedicated for the next scheduled dose. Participants who develop Grade 2 toxicitiy despite adequate premedication should be permanently discontinued from further study intervention.
Pembrolizumab Administration
[0564] Pembrolizumab will be administered as a 30-minute IV infusion on Day 1 of every treatment cycle if given Q3W or on Day 1 of every other treatment cycle if given Q6W. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window of −5 minutes and +10 minutes is permitted (i.e, infusion time is 30 minutes: −5 min/+10 min).
Pembrolizumab with MK-1308, a CTLA4 Antagonist
[0565] An ongoing, multicenter, multi-arm, open-label Phase 1b study (MK-1308-001) is evaluating MK-1308 (a CTLA4 antagonist) in combination with pembrolizumab in participants with solid tumors (NCT03179436). In dose escalation, MK-1308 was given at either 25 mg or 75 mg (Cohorts 1 and 2) IV Q3W as monotherapy × 1 cycle, in combination with pembrolizumab 200 mg Q3W×4 cycles, followed by pembrolizumab monotherapy. In dose confirmation, participants with 1 L advanced NSCLC were treated with MK-1308 at 25 mg Q3W (Arm A), 25 mg Q6W (Arm B), or 75 mg Q6W (Arm C), in combination with pembrolizumab 200 mg Q3W. Response was assessed Q9W.
[0566] This first-in-human study of MK-1308 was designed to assess the safety, tolerability, PK, and pharmacodynamics of escalating doses of MK-1308 when used in combination with pembrolizumab in participants with advanced/metastatic solid tumors refractory to conventional therapy, 1 L treatment-naïve NSCLC, and 2 L SCLC. It is reasonable to expect the PK of MK-1308 to be consistent with that of other humanized mAbs that typically have a low clearance and a limited volume of distribution. Using a population PK model of ipilimumab, distribution of exposures from the 25 mg MK-1308 fixed dose overlapped considerably with those obtained with the 0.3 mg/kg weight-based ipilimumab dose, and exposures from the 75 mg MK-1308 fixed dose overlapped considerably with those obtained with the 1.0 mg/kg weight-based ipilimumab dose [Feng, Y., et al 2014]. Similar to pembrolizumab, a fixed-dose regimen of MK-1308 is expected to reduce complexity in the logistical chain at treatment facilities and to reduce waste. The goal in introducing the lower doses of 25 mg MK-1308 at the schedule of either Q3W or Q6W was to determine if a similar response rate could be achieved at lower doses, which would be expected to result in a reduction in immune-related toxicities from CTLA-4 antagonism. The goal in evaluating the 75 mg MK-1308 dose at the Q6W interval was to achieve the expected response rates with similar acceptable toxicity and discontinuation rates based on the Phase 1 CheckMate-012 results in the NSCLC population [Hellmann, M. D., et al 2016]. Details regarding specific benefits and risks for participants participating in this clinical study may be found in the Investigator's Brochure (IB) and informed consent documents.
[0567] Participants with advanced melanoma that is refractory to PD-1/L1 are planned to be enrolled in this study in the efficacy expansion phase based on the following evidence: (1) improved response rates after ipilimumab/nivolumab in the Checkmate 067 study; (2) improved response rates after treatment with ipilimumab/pembrolizumab in the KEYNOTE-029 study and; (3) the results from a Merck single-institution collaborative study in a similar melanoma population [Wolchok, J. D., et al 2017] [Long, G. V., et al 2017] [Olsonm, D., et al 2018].
[0568] An interim analysis of MK-1308 safety, antitumor activity, pharmacokinetic (PK), and pharmacodynamic biomarker data was performed for the Dose Escalation and Dose Confirmation phases of the study based on a 7 Nov. 2018 database lock. The ORR by blinded independent central review (BICR) with confirmation for MK-1308 25 mg administered Q6W in the advanced 1 L NSCLC population (Arm B) was similar to the ORR for the 75 mg dose level given Q6W (33% versus 22%, respectively). The target rate for DLT was not reached in any of Cohorts 1, 2, or 3; however, a higher toxicity rate correlated with a higher MK-1308 dose among several different AE characteristics, including drug-related AEs, Grade 3 to 5 AEs, SAEs, and AEs leading to treatment discontinuation or modification. The Grade 3 to 5 AE rate was 29% in Cohort 1, 71% in Cohort 2, and 100% in Cohort 3. In the Dose Confirmation phase, a lower MK-1308 dose and a longer treatment interval had a more favorable toxicity profile (45% in Arm B, 48% in Arm A, 53% in Arm C, and 86% in Arm E [MK-1308 75 mg in combination with pembrolizumab 200 mg Q3W]). Time to first Grade 3 to 5 AE was more rapid at a higher MK-1308 dose and with more frequent dosing (7 months in Arm B, 5.2 months in Arm A, 5.6 months in Arm C, and 1.1 month in Arm E). The most common AEs were fatigue (24.9%), pruritus (24.4%), rash (23.5%), decreased appetite (22.5%), AST increased (19.2%), ALT increased (17.4%), diarrhea (16.4%), and hypothyroidism (16%). In totality, the efficacy, safety, and PK data led to the selection of 25 mg given Q6W as the RP2D for MK-1308 for use in combination with pembrolizumab.
Pembrolizumab with Lenvatinib
[0569] E7080-A001-111/KEYNOTE-146 is an ongoing multicohort Phase 2 study to assess the efficacy and safety of lenvatinib in combination with pembrolizumab in 6 types of biomarker-unselected metastatic solid tumors, including melanoma (excluding uveal melanoma), that have progressed after treatment with approved therapies or for which there are no standard effective therapies available. The study is ongoing but is no longer enrolling melanoma patients. Eligible patients are aged 18 years or older and have histologically confirmed nonuveal melanoma, 0 to 2 prior systemic anticancer regimens, and an ECOG score of 0 or 1. The primary endpoint is ORR at Week 24 based on iRECIST, as determined by investigator-read tumor assessments performed at baseline, Q6W until Week 24, and then Q9W thereafter. Secondary endpoints include Objective Response Rate (ORR), Duration of Response (DOR), Progression-free Survival (PFS), Overall Survival (OS), and safety and tolerability of the combination. All participants received lenvatinib 20 mg daily in combination with 200 mg pembrolizumab IV Q3W. At data cutoff (1 Mar. 2018), 21 metastatic melanoma patients were enrolled, and 38% of participants had 1 or more prior anticancer therapy.
[0570] For all enrolled participants (N=21), the ORR at Week 24 was 47.6% (95% CI: 25.7, 70.2) using iRECIST by investigator review. Of the 10 confirmed responses, 9 (42.9%) were PR, and 1 (4.8%) was CR. Stable disease was observed in 7 (33.3%) participants, and 3 (14.3%) experienced progressive disease. One participant had an unknown response. Median duration of objective response was 12.5 months (95% CI, 2.7 months, NE). Median PFS observed was 7.6 months (95% CI: 2.6 months, 15.8 months).
[0571] All participants experienced ≥1 treatment-related AE. There were no fatal treatment-related AEs. The most common any-grade treatment-related AEs were fatigue (52%), decreased appetite (48%), diarrhea (48%), hypertension (48%), dysphonia (43%), and nausea (43%). Dose reduction and interruption due to treatment-related AEs occurred in 13 (62%) and 10 (47.6%) participants, respectively. The safety profile of lenvatinib in combination with pembrolizumab appears manageable in patients with malignant melanoma and other tumor types and is consistent with each agent's safety profile when administered as monotherapy.
Pembrolizumab, MK-1308, and Lenvatinib
[0572] The primary objective is to assess the safety and tolerability of investigational treatment combinations (MK-1308 in combination with pembrolizumab and lenvatinib) based on the proportion of participants with adverse events, and to evaluate the objective response rates (ORR) as assessed by blinded independently central review per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).
[0573] The secondary objective is to evaluate the duration of response (DOR) as assessed by BICR per RECIST 1.1. DOR is defined as the time from the first documented evidence of complete response (CR) or partial response (PR) until disease progression or death due to any cause, whichever occurs first.
[0574] The tertiary/exploratory objectives include the evaluation of progression-free survival (PFS) as assessed by BICR per RECIST 1.1. PFS is the time from the date of randomization/allocation to the date of the first documentation of disease progression or death from any cause, whichever occurs first. Additionally, this study will be used to evaluate overall survival (OS). OS is the time from the date of randomization/allocation to the date of death from any cause. ORR is evaluated as assessed by the investigator per RECIST 1.1 (and per RECIST 1.1 for Immune Based Therapeutics (iRECIST)). An objective of this study is to characterize the pharmacokinetic (PK) profile of each agent in the example, the development of circulating antidrug antibodies, of each agent, following administration, and to identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, and/or mechanism of action of pembrolizumab, MK-1308, and lenvatinib. The study will also be used to assess the score change from baseline and the time to true deterioration (TTD) in patient-reported outcomes (PRO) scores in global health status/quality of life (QoL) and physical functioning, to evaluate health status as assessed by the European Quality of Life 5-dimension 5-level (EQ-5D-5L) questionnaire to generate utility scores, and to assess the effects of therapy on tumor growth kinetics.
[0575] RECIST 1.1 is used by the BICR when assessing images for efficacy measures and by the local site when determining eligibility. Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been developed and published by the RECIST Working Group, with input from leading experts from industry and academia, along with participation from the US Food and Drug Administration and the European Medicines Agency. The unidimensional measurement of target lesions, qualitative assessment of non-target lesions, and response categories are identical to RECIST 1.1, until progression is seen by RECIST 1.1. However, if a participant is clinically stable, additional imaging may be performed to confirm radiographic progression. iRECIST is used by investigators to assess tumor response and progression and to make treatment decisions as well as for exploratory efficacy analyses where specified.
[0576] Male/female participants with melanoma who are at least 18 years of age are enrolled in this study. A maximum of approximately 100 participants will be enrolled. The participant population is PD-1 refractory melanoma.
[0577] After a Screening Phase of up to 28 days, each participant will receive study intervention for approximately 2 years or until disease progression is radiographically documented per RECIST 1.1 by the investigator, unacceptable AEs, withdrawal of consent or death, intercurrent illness that prevents further administration of study intervention, investigator's decision to discontinue the participant, noncompliance with study intervention or procedure requirements, or administrative reasons requiring cessation of study intervention, whichever occurs first. Participants who attain an investigator-determined confirmed complete response (CR) may consider stopping study intervention after at least 24 weeks of study intervention has been administered. In addition, if a confirmed CR per RECIST 1.1 is attained, at least 2 additional doses of study intervention must be received after CR is first documented.
[0578] Participants will be permitted to continue study intervention beyond RECIST 1.1-defined disease progression as long as the treating investigator considers that the participant may experience clinical benefit with continued intervention, and the participant is tolerating study intervention as per iRECIST (RECIST 1.1 for immune-based therapeutics). Treatment beyond disease progression per iRECIST may be permitted upon Sponsor consultation and approval.
[0579] After the End of Treatment (EOT), each participant will be followed for the occurrence of AEs and spontaneously reported pregnancy.
[0580] Participants who discontinue due to radiographic disease progression will move into posttreatment Safety and Survival Follow-up. Participants who discontinue for reasons other than radiographic disease progression will have posttreatment Safety and Follow-up imaging for disease status until disease progression is documented radiographically per RECIST 1.1 by the investigator, a nonstudy cancer treatment is initiated, consent is withdrawn, pregnancy, death, or becoming lost to follow-up. All participants will be followed for overall survival (OS) until death, withdrawal of consent, or the end of this study.
[0581] This study will include participants with PD-1 refractory melanoma. PD-1 refractory melanoma must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. Participants must have received at least 2 doses of an approved anti-PD-1/L1 mAb and have demonstrated disease progression after PD-1/L1 as defined by RECIST 1.1. No approved therapies exist in this setting and therefore, this population is considered as having a high need.
[0582] This study will consist of 1 or more investigational treatment arms evaluating pembrolizumab based/non-pembrolizumab-based combinations. If more than 1 investigational treatment arm is open at any given time, participants will be randomly assigned to 1 of the investigational treatment arms open for enrollment.
[0583] This study will only consist of an Efficacy Phase once the RP2D of a combination has been established in a separate Phase 1 study. However, when the RP2D of the combination has not previously been established (i.e, pembrolizumab combined with 2 or more investigational agents), this study will have 2 phases: an initial Safety Lead-in Phase, in which the preliminary RP2D of the combination will be established, followed by an Efficacy Phase.
Efficacy Endpoints
[0584] The primary efficacy objective of this study is to evaluate the antitumor effect of various investigational agents with or without pembrolizumab in participants with PD-1 refractory melanoma.
[0585] This study will use objective response as the primary efficacy endpoint. Objective response rate is defined as the proportion of participants who have best response as CR or PR. Responses are based on BICR using RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). Objective response rate is an appropriate endpoint to evaluate the antitumor activity of investigational treatment arms.
[0586] A treatment effect measured by ORR can support accelerated approval, support traditional approval, or represent direct clinical benefit based on the specific disease, context of use, magnitude of the effect, number of CRs, durability of response, disease setting, location of the tumors, available therapy, and risk-benefit relationship.
[0587] This study will use DOR as a secondary efficacy endpoint. Duration of response is defined as the time from the earliest date of qualifying response until the earliest date of disease progression or death from any cause, whichever comes first. Duration of response per RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, assessed by BICR will serve as an additional measure of efficacy and is a commonly accepted endpoint by both regulatory authorities and the oncology community.
[0588] This study will use PFS as an exploratory efficacy endpoint. Progression-free survival is defined as the time from date of randomization/allocation until the first date of disease progression or death from any cause, whichever comes first, based on RECIST 1.1 criteria as assessed by BICR. Images will be read by a central imaging vendor blinded to treatment assignment to minimize bias in the response assessments. Progression-free survival can reflect tumor growth and be assessed before the determination of a survival benefit. Its determination is not confounded by subsequent therapy. Treatment effect measured by PFS can be a surrogate endpoint to support accelerated approval, a surrogate endpoint to support traditional approval, or it can represent direct clinical benefit based on the specific disease, context of use, magnitude of the effect, the disease setting, location of metastatic sites, available therapy, the risk-benefit relationship, and the clinical consequences of delaying or preventing progression in key disease sites (e.g., delay of new lesions in the brain or spine) or delaying administration of more toxic therapies. This study will also evaluate ORR as assessed by investigator per RECIST 1.1 as an exploratory endpoint.
[0589] Additionally, this study will use OS as an exploratory efficacy endpoint. Overall survival has been recognized as the gold standard for the demonstration of superiority of a new antineoplastic therapy in randomized clinical studies. Overall survival in this study is defined as the time from date of randomization/allocation to death from any cause.
Inclusion Criteria
[0590] Participants are eligible to be included in the study only if all the of following apply: [0591] 1. Has histologically or cytologically confirmed melanoma. [0592] 2. Has unresectable Stage III or Stage IV melanoma, per AJCC 8th Edition Staging Criteria (see Appendix 9), not amenable to local therapy. [0593] 3. Has the presence of at least 1 measurable lesion by CT or MRI per RECIST 1.1 as confirmed by BICR. [0594] a. Cutaneous lesions and other superficial lesions are not considered measurable lesions but may be considered as nontarget lesions. [0595] b. If participants have only 1 measurable lesion per RECIST 1.1, the biopsy specimen should be obtained from the nontarget lesion or archival tissue. If biopsy specimen was obtained from a lone target lesion, a repeat screening CT must be obtained post biopsy and measurable disease confirmed by BICR. [0596] c. Lesions that are in an area that has been previously irradiated should not be considered measurable unless there has been documented growth of the lesions since the completion of radiation. [0597] 4. Has progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria: [0598] a. Received at least 2 doses of an approved anti-PD-1/L1 mAb. [0599] b. Demonstrated disease progression after PD-1/L1 as defined by RECIST 1.1. The initial evidence of disease progression is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented progressive disease, in the absence of rapid clinical progression. This determination is made by the investigator. Once progressive disease is confirmed per iRECIST by the investigator, the initial date of progressive disease documentation will be considered the date of disease progression. [0600] c. Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb. [0601] d. Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of Stage III or IV melanoma and have disease recurrence (unresectable loco-regional disease or distant metastases) while on active treatment or within 6 months of stopping anti-PD-1. For these participants, the following applies: 1) a second assessment to confirm disease progression beyond recurrence is not required; and 2) they must have received at least 2 prior doses of anti-PD-1/L1 mAb. This participant population may be limited to approximately 20% in each investigational treatment arm. [0602] e. Prior therapy with CTLA-4 inhibitors will not be allowed. [0603] 5. Has submitted prestudy imaging. Note: The site's study team must have reviewed prestudy images that are of diagnostic quality from at least 3 dates to determine that radiographic progression has occurred per RECIST 1.1/iRECIST following initiation of an anti-PD-1/L1 agent. The CIV must have received these scans and have confirmed that they are of acceptable diagnostic quality prior to treatment randomization/allocation in this study for a retrospective analysis of Inclusion Criterion 4: participants must be refractory to anti-PD-1/L1 agents. The CIV will not be confirming this eligibility criterion prior to treatment randomization/allocation. [0604] 6. Has not received more than 3 lines of therapy for their advanced melanoma. [0605] 7. Has provided a tumor biopsy. [0606] a. Participants must submit tumor sample during Screening for confirmation of adequacy of tumor tissue at a central pathology laboratory. Participants who do not submit a tumor tissue sample will not be randomized/allocated. [0607] b. Tumor sample should be freshly obtained (strongly preferred). In cases where newly obtained tissue is not possible to provide; an archival sample may be acceptable after discussion with the Sponsor. Only archival samples that have been obtained after progression on a PD-1/L1 agent will be accepted. [0608] c. If a fresh tissue sample is submitted, it is preferred that the tumor biopsy is not obtained from a lone target lesion. If the biopsy specimen was obtained from a lone target lesion, a repeat screening CT must be obtained post-biopsy and measurable disease confirmed by BICR. [0609] 8. Male Participants—Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of lenvatinib: [0610] a. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent, or [0611] b. Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as below: [0612] i. Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a women of childbearing potential (WOCBP) who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration. [0613] 9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies: [0614] a. Is not a WOCBP, or [0615] b. Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix 5 during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. The investigator should evaluate the potential for contraceptive method failure (i.e, noncompliance, recently initiated) in relationship to the first dose of study intervention [0616] A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention. [0617] If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. [0618] The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Exclusion Criteria
[0619] The participant must be excluded from the study if the participant:
Medical Conditions
[0620] 1. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study intervention. Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. [0621] 2. Has a known additional malignancy that is progressing or requires active treatment within the past 2 years. Exceptions to the secondary malignancy exclusion include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, new nonulcerated primary melanoma <1 mm in depth with no nodal involvement, Grade 1 follicular lymphoma or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy. [0622] 3. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated CNS metastases may participate provided they are stable (without evidence of progression by imaging prior to the first dose of study intervention as evidenced by 2 scans at least 4 weeks apart providing stability, and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases confirmed by repeat imaging, and have not required steroids for at least 14 days before study intervention. The second scan showing stability may be used as baseline scan if acquired within the Screening Phase. [0623] Note: Participants with asymptomatic previously untreated brain metastases may participate provided there are ≤3 total lesions in the brain and their longest diameter is <1 cm. Stability of these lesions does not need to be confirmed by repeat imaging. Baseline MRI brain scan will be obtained for all participants. Brain CT scan should only be used when MRI is contraindicated. The second brain MRI showing stability may be used as baseline scan if acquired within the Screening Phase. [0624] 4. Has ocular or mucosal melanoma. [0625] 5. Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another mAb. For a list of excipients, refer to the respective IB. [0626] 6. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. [0627] 7. Has an active infection requiring systemic therapy. [0628] 8. Has known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). No testing of HIV is required unless mandated by local health authority (see Appendix 11 for country-specific requirements). [0629] 9. Has known history of hepatitis B (defined as HBsAg reactive) or known hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority (see Appendix 11 for country-specific requirements). [0630] 10. Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis. [0631] 11. Has a history of active tuberculosis (TB; Bacillus tuberculosis). (See Appendix 11 for country-specific requirements). [0632] 12. A WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization or treatment allocation (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: In the event that more than 24 hours have elapsed between the Screening pregnancy test and the first dose of study intervention, another pregnancy test (urine or serum) must be performed and must be negative in order for the participant to start receiving study intervention.
Prior/Concomitant Therapy
[0633] 13. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization/allocation. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy and/or ≤Grade 2 endocrinopathy may be eligible. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study intervention. [0634] 14. Has received prior radiotherapy within 2 weeks of first dose of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. [0635] 15. Has had major surgery (<3 weeks prior to first dose of study intervention) Note: If the participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to first dose of study intervention. Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility. [0636] 16. Has received a live vaccine within 30 days before the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
[0637] 17. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. Note: Participants who have entered the Follow-up phase of an investigational study may participate if it has been 4 weeks since the last dose of the previous investigational agent.
Other Exclusions
[0638] 18. Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. [0639] 19. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening visit through 120 days after the last dose of study intervention. [0640] 20. Has had an allogeneic tissue/solid organ transplant. [0641] 21. Has a pre-existing Grade ≥3 gastrointestinal or nongastrointestinal fistula. [0642] 22. Has radiographic evidence of encasement of invasion of a major blood vessel, or of intratumoral cavitation. Note: the degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy. [0643] 23. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study intervention. [0644] 24. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted. [0645] 25. Has urine protein ≥1 g/24-hour. Note: Participants having >1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. [0646] 26. Has prolongation of QTc interval (calculated using Fridericia's formula) to >480 msec. [0647] 27. Has LVEF below the institutional normal range as determined by MUGA or echocardiogram. [0648] 28. Has presence of gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib. [0649] 29. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
Dose Limiting Toxicity
[0650] Dose-limiting toxicities will be defined from toxicities observed during the first cycle of the Safety Lead-in Phase. The occurrence of any of the following toxicities will be considered a DLT unless the investigator assessment determines the toxicity to be clearly not related to the study intervention: [0651] Grade 4 nonhematologic toxicity (not laboratory) [0652] Grade 4 hematologic toxicity lasting >=7 days, except [0653] Grade 4 platelet count decreased of any duration [0654] Grade 3 platelet count decreased if associated with bleeding [0655] Grade 4 lymphopenia lasting ≥21 days [0656] Any nonhematologic AE>=Grade 3 (not laboratory) lasting >3 days despite optimal supportive care [0657] Any Grade 3 or Grade 4 clinically significant nonhematologic laboratory abnormality, if: [0658] medical intervention is required to treat the participant, or [0659] the abnormality leads to hospitalization, or [0660] the abnormality persists for >1 week [0661] any febrile neutropenia Grade 3 or Grade 4 [0662] Any treatment related AE that causes the participant to discontinue study intervention during the DLT window [0663] Any Grade 5 toxicity [0664] Any treatment-related toxicity that causes a >2 week delay in initiation of Cycle 3
Assessment at Screening and Prior to RECIST 1.1 Progression
[0665] Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST assessment.
Assessment and Decision at RECIST 1.1 Progression
[0666] For participants who show evidence of radiological progressive disease by RECIST 1.1 as determined by the investigator, the investigator will decide whether to continue a participant on study intervention until repeat imaging is obtained (using iRECIST for participant management). This decision by the investigator should be based on the participant's overall clinical condition.
Clinical stability is defined as the following: [0667] Absence of symptoms and signs indicating clinically significant progression of disease [0668] No decline in ECOG performance status [0669] No requirements for intensified management, including increased analgesia, radiation, or other palliative care
[0670] Any participant deemed clinically unstable should be discontinued from study intervention at site-assessed first radiologic evidence of progressive disease and is not required to have repeat tumor imaging for confirmation of progressive disease by iRECIST.
[0671] If the investigator decides to continue treatment, the participant may continue to receive study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm progressive disease by iRECIST, per investigator assessment. Images should continue to be sent in to the central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including: [0672] Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and [0673] ≥5 mm from nadir [0674] Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum of diameters” will be used in this protocol, consistent with the original RECIST 1.1 terminology. [0675] Unequivocal progression of nontarget lesion(s) identified at baseline [0676] Development of new lesion(s)
[0677] iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors caused the progression.
[0678] At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be assessed as usual.
[0679] New lesions will be classified as measurable or non-measurable using the same size thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions—Target. The sum of diameters of these lesions will be calculated and kept distinct from the sum of diameters for target lesions at baseline. All other new lesions will be followed qualitatively as New Lesions—Nontarget.
Assessment at the Confirmatory Imaging
[0680] On the confirmatory imaging, the participant will be classified as progression confirmed (with an overall response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
[0681] Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following occurs: [0682] Any of the factors that were the basis for the iUPD at the previous visit show worsening [0683] For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, compared to any prior iUPD time point [0684] For nontarget lesions, worsening is any significant growth in lesions overall, compared to a prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1 [0685] For new lesions, worsening is any of these: [0686] An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time point [0687] Visible growth of new nontarget lesions [0688] The appearance of additional new lesions [0689] Any new factor appears that would have triggered progressive disease by RECIST 1.1
Persistent iUPD
[0690] Progression is considered not confirmed, and the overall response remains iUPD, if: [0691] None of the progression-confirming factors identified above occurs AND [0692] The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold (by RECIST 1.1)
[0693] Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on which iUPD is seen. This may correspond to the next visit in the original visit schedule. The assessment of the subsequent confirmation imaging proceeds in an identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
[0694] Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: [0695] None of the progression-confirming factors identified above occurs, AND [0696] The target lesion sum of diameters (initial target lesions) is not above the initial progressive disease threshold.
[0697] The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR if all lesions resolve.
[0698] In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for progression is “reset.” This means that the next visit that shows radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
[0699] If repeat imaging does not confirm progressive disease per iRECIST, as assessed by the investigator, and the participant continues to be clinically stable, study intervention may continue and follow the regular imaging schedule. If progressive disease is confirmed, participants will be discontinued from study intervention.
Detection of Progression at Visits after Pseudo-Progression Resolves
[0700] After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by any of the following events: [0701] Target lesions [0702] Sum of diameters reaches the progressive disease threshold (≥20% and ≥5 mm increase from nadir) either for the first time, or after resolution of previous pseudo-progression. The nadir is always the smallest sum of diameters seen during the entire substudy, either before or after an instance of pseudo-progression. [0703] Nontarget lesions [0704] If nontarget lesions have never shown unequivocal progression, their doing so for the first-time results in iUPD. [0705] If nontarget lesions have shown previous unequivocal progression, and this progression has not resolved, iUPD results from any significant further growth of non-target lesions, taken as a whole. [0706] New lesions [0707] New lesions appear for the first time [0708] Additional new lesions appear [0709] Previously identified new target lesions show an increase of ≥5 mm in the new lesion sum of diameters, from the nadir value of that sum [0710] Previously identified nontarget lesions show any significant growth
[0711] If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.
[0712] Progression must be confirmed before iCPD can occur. The decision process is identical to the iUPD confirmation process for the initial progressive disease, with 1 exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory imaging the burden of new lesions has increased from its smallest value (for new target lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et al 2017].
AJCC 8.SUP.th .Edition Staging Criteria and Overall Staging Table
[0713] The AJCC has designated staging by TNM classification to define melanoma. The following staging tables (Tables 21-24) adapted from AJCC 8th edition. Refer to AJCC guidelines for more information [Gershenwald, J. E., et al 2017]. ECOG performance status is listed in Table 25.
TABLE-US-00021 TABLE 21 Melanoma T Category Definition T Stage T Stage Definition (thickness and ulceration) TX Primary tumor thickness cannot be assessed (ulceration status not applicable) T0 No evidence of primary tumor (ulceration status not applicable) Tis Melanoma in situ (ulceration status not applicable) T1 ≤1.0 mm (ulceration status unknown or unspecified) T1a <0.8 mm without ulceration T1b <0.8 mm with ulceration or 0.8-1.0 mm with or without ulceration T2 >1.0-2.0 mm (ulceration status unknown or unspecified) T2a >1.0-2.0 mm without ulceration T2b >1.0-2.0 mm with ulceration T3 >2.0-4.0 mm (ulceration status unknown or unspecified) T3a >2.0-4.0 mm without ulceration T3b >2.0-4.0 mm with ulceration T4 >4.0 mm (ulceration status unknown or unspecified) T4a >4.0 mm without ulceration T4b >4.0 mm with ulceration Abbreviations: T = primary tumor.
TABLE-US-00022 TABLE 22 Melanoma N Category Definition N Number of Tumor-involved Presence of In-transit, Satellite, Category Regional Lymph Nodes and/or Microsatellite Metastases NX Regional Nodes not assessed (exception: No pathological N category not required for T1 melanomas, use clinical N information) N0 No regional metastases detected No N1 One tumor-involved node or any number of in- transit, satellite, and/or microsatellite metastases with no tumor-involved nodes N1a One clinically occult (detected by SLN biopsy) No N1b One clinically detected No N1c No regional lymph node disease Yes N2 2 or 3 tumor-involved nodes or any number of in-transit, satellite, and/or micro-satellite metastases with 1 tumor-involved node N2a 2 or 3 clinically occult (detected by SLN biopsy) No N2b 2 or 3, at least one of which was clinically detected No N2c One clinically occult or clinically detected Yes N3 Four or more tumor-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with 2 or more tumor-involved nodes, or any number of matted nodes without or with in- transit, satellite, and/or microsatellite metastases. N3a 4 or more clinically occult (detected by SLN biopsy) No N3b 4 or more, at least one of which was clinically No detected, or the presence of any number of matted nodes N3c 2 or more clinically occult or clinically detected Yes and/or presence of any number of matted nodes. Abbreviations: N = regional lymph node; SLN = sentinel lymph node.
TABLE-US-00023 TABLE 23 Melanoma M Category Definition M Category Anatomic Site Lactate Dehydrogenase Level M0 No evidence of distant metastasis Not applicable M1 Evidence of distant metastasis See below M1a Distant metastasis to skin, soft tissue Not recorded or unspecified including muscle, and/or nonregional lymph node M1a(0) Not elevated M1a(1) Elevated M1b Distant metastasis to lung with or without Not recorded or unspecified M1a sites of disease M1b(0) Not elevated M1b(1) Elevated M1c Distant metastasis to noncentral nervous Not recorded or unspecified system visceral sites with or without M1a or M1b sites of disease M1c(0) Not elevated M1c(1) Elevated Mid Distant metastasis to CNS with or without Not recorded or unspecified M1a, M1b, or M1c sites of disease M1d(0) Not elevated M1d(1) Elevated Abbreviations: CNS = central nervous system; M = distant metastasis.
TABLE-US-00024 TABLE 24 AJCC Pathological (pTNM) Staging Groups Staging (AJCC 8th edition) 0 Tis N0 M0 IA T1a N0 M0 IA T1b N0 M0 IB T2a N0 M0 IIA T2b N0 M0 IIA T3a N0 M0 IIB T3b N0 M0 IIB T4a N0 M0 IIC T4b N0 M0 IIIB T0 N1b, N1c M0 IIIC T0 N2b, N2c, N3b, N3c M0 IIIA T1a/b-T2a N1a or N2a M0 IIIB T1a/b-t2a N1b/c orN2b M0 IIIB T2b/T3a N1a-N2b M0 IIIC T1a-T3a N2c or N3a/b/c M0 IIIC T3b/T4a Any N ≥ N1 M0 IIIC T4b N1a-N2c M0 IIID T4b N3a/b/c M0 IV Any T, Tis Any N M1 Abbreviations: M0 = No evidence of distant metastases; N0 = No regional metastasis detected including no tumor-involved nodes and no in-transit, satellite, and/or microsatellite metastasis; pTNM = pathological tumor, nodes, and metastasis.
TABLE-US-00025 TABLE 25 ECOG Performance Status Grade Description 0 Normal activity. Fully active, able to carry on all predisease performance without restriction. 1 Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). 2 In bed <50% of the time. Ambulatory and capable of all self- care, but unable to carry out any work activities. Up and about >50% of waking hours. 3 In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 Dead. Abbreviations: ECOG = Eastern Cooperative Oncology Group Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., Carbone, P. P.: Toxicity and Response Criteria of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
Discontinuation of Study Intervention and Participant Withdrawal
[0714] Discontinuation of study intervention does not represent withdrawal from the study. As certain data on clinical events beyond study intervention discontinuation may be important to the study, they must be collected through the participant's last scheduled follow-up, even if the participant has discontinued study intervention. Therefore, all participants who discontinue study intervention prior to completion of the specified treatment period will continue to participate in the study.
[0715] Participants may discontinue study intervention at any time for any reason or be discontinued from the study intervention at the discretion of the investigator should any untoward effect occur. In addition, a participant may be discontinued from study intervention by the investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or for administrative and/or other safety reasons.
[0716] A participant must be discontinued from study intervention but continue to be monitored in the study for any of the following reasons:
The participant or participant's legally acceptable representative requests to discontinue study intervention. [0717] The participant has a medical condition or personal circumstance which, in the opinion of the investigator and/or Sponsor, placed the participant at unnecessary risk from continued administration of study intervention. [0718] The participant has a confirmed positive serum pregnancy test. [0719] Documented disease progression. Note: Participants will be permitted to continue treatment beyond documented RECIST 1.1-defined progression if investigator-assessed clinical stability is observed, and the participant is tolerating study intervention. Treatment beyond progressive disease per iRECIST may be permitted in this study following Sponsor consultation and approval. A description of the adaptations and iRECIST process is provided in Appendix 8, with additional details in the iRECIST publication [Seymour, L., et al 2017]. [0720] Any progression or recurrence of any malignancy, or any occurrence of another malignancy, which requires active treatment. Exceptions to secondary malignancy include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, new nonulcerated primary melanoma <1 mm in depth with no nodal involvement, Grade 1 follicular lymphoma or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy. Exceptions should be discussed with the Sponsor prior to continuing therapy. [0721] Recurrent Grade 2 pneumonitis and other AEs that may require treatment discontinuation (Dose Modification). [0722] Completion of approximately 2 years of study intervention.
Informed Consent
[0723] The investigator or medically qualified designee (consistent with local requirements) must obtain documented consent from each potential participant or each participant's legally acceptable representative prior to participating in a clinical study. If there are changes to the participant's status during the study (e.g., health or age of majority requirements), the investigator or medically qualified designee must ensure the appropriate consent is in place.
Tumor Imaging and Assessment of Disease
[0724] The process for image collection and transmission to the CIV can be found in the site imaging manual.
[0725] Diagnostic quality CT of the chest, abdomen, pelvis, and neck (if disease present) is required at baseline and at all scheduled follow-up visits. Tumor imaging is strongly preferred to be acquired by CT; the CT portion of PET/CT may be used in place of stand-alone CT if it is of diagnostic quality per the Site Imaging Manual. If a site's standard practice is to follow participants with PET/CT rather than a dedicated CT, these initial images must show progression on prior anti-PD-1/L1 inhibitor, consistent with RECIST 1.1 and iRECIST. There will be no allowance for “worsening of existing disease” by PET if there is NO new lesion. There must be a NEW lesion seen either on PET/CT, or diagnostic quality CT. Refer to the Site Imaging Manual for additional information.
[0726] For the abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or when mandated by local practice. Magnetic resonance imaging is the strongly preferred modality for imaging the brain. The same imaging technique regarding modality, ideally the same scanner, and the use of contrast should be used in a participant throughout this study to optimize the reproducibility of the assessment of existing and new tumor burden and improve the accuracy of the assessment of response or progression based on imaging. Note: for the purposes of assessing tumor imaging, the term “investigator” refers to the local investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
[0727] Brain imaging is required for all participants at Screening. Magnetic resonance imaging is preferred; however, CT imaging will be acceptable, if MRI is medically contraindicated.
[0728] All scheduled images performed at Screening for all study participants from the sites will be submitted to the CIV to verify the presence of measurable disease by BICR per RECIST 1.1 prior to randomization. All subsequent scheduled images for all study participants from the sites will be submitted to the CIV. In addition, images (including via other modalities) that are obtained at an unscheduled time point to determine disease progression, as well as imaging obtained for other reasons, and captures radiologic progression based on investigator assessment, should also be submitted to the CIV.
Initial Tumor Imaging
[0729] Initial tumor imaging at Screening must be performed within 28 days prior to the date of the first dose of study intervention. If additional time is needed for initial image submission (screening imaging for real-time confirmation of measurable disease per RECIST 1.1 by BICR) and CIV diagnostic quality review (for real-time quality review of prestudy images by BICR), an extension of the screening window of up to 7 days may be approved following mandatory Sponsor consultation. Tumor imaging performed as part of routine clinical management is acceptable for use as Screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to the first dose of study intervention.
[0730] Participants in this study with previously treated brain metastases may participate provided they have stable brain metastases, i.e, without evidence of progression by imaging (confirmed by MRI if MRI was used at prior imaging or confirmed by CT imaging if CT used at prior imaging prior to the first dose of study intervention as evidenced by 2 scans at least 4 weeks apart providing stability).
Tumor Imaging During the Study
[0731] The first on-study imaging assessment should be performed at 9 weeks (63 days±7 days) from the date of randomization. Subsequent tumor imaging should be performed every 9 weeks (63 days±7 days) for the first year (until Week 52), after which the imaging interval increases to every 12 weeks (84 days±7 days) for −2 years (until Week 104); and Q24W thereafter or sooner if clinically indicated. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts. Imaging should continue to be performed until disease progression is identified by the investigator per RECIST 1.1 unless the investigator elects to continue treatment and follow iRECIST, the start of new anticancer treatment, withdrawal of consent, or death, whichever occurs first. All supplemental imaging must be submitted to the CIV.
[0732] Per iRECIST, disease progression should be confirmed by the site 4 to 8 weeks after site-assessed first radiologic evidence of progressive disease in clinically stable participants. Participants who have unconfirmed disease progression may continue on treatment at the discretion of the investigator until progression is confirmed by the site. Participants who receive confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point, if clinically stable. Participants who have confirmed disease progression by iRECIST, as assessed by the site, will discontinue study intervention.
End of Treatment and Follow Up Tumor Imaging
[0733] For participants who discontinue study intervention, tumor imaging should be performed at the time of treatment discontinuation (±4-week window). If previous imaging was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not mandatory. For participants who discontinue study intervention due to documented disease progression, this is the final required tumor imaging if the investigator elects not to implement iRECIST.
[0734] For participants who discontinue study intervention without documented disease progression, every effort should be made to continue monitoring disease status by tumor imaging using the same imaging schedule used while on treatment (every 9 weeks for the first year [through Week 52] and approximately every 12 weeks after Year 1) until the start of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the end of this study, whichever occurs first.
RECIST 1.1 Assessment of Disease
[0735] RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease progression, and as a basis for all protocol guidelines related to disease status (e.g., discontinuation of study intervention). Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
[0736] iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor response and progression and make treatment decisions. When clinically stable, participants should not be discontinued until progression is confirmed by the investigator. This allowance to continue treatment despite initial radiologic progressive disease takes into account the observation that some participants can have a transient tumor flare in the first few months after the start of immunotherapy, and then experience subsequent disease response. This data will be captured in the clinical database.
[0737] Any participant deemed clinically unstable should be discontinued from study intervention at central verification of site-assessed first radiologic evidence of progressive disease and is not required to have repeat tumor imaging for confirmation of progressive disease by iRECIST.
[0738] If the investigator decides to continue treatment, the participant may continue to receive study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm progressive disease by iRECIST, per investigator assessment. Images should continue to be sent in to the central imaging vendor for potential retrospective BICR.
[0739] If repeat imaging does not confirm progressive disease per iRECIST, as assessed by the investigator, and the participant continues to be clinically stable, study intervention may continue and follow the regular imaging schedule. If progressive disease is confirmed, participants will be discontinued from study intervention.
[0740] If a participant has confirmed radiographic progression (iCPD), study intervention should be discontinued; however, if the participant is achieving a clinically meaningful benefit, an exception to continue study intervention may be considered following consultation with the Sponsor.
[0741] A summary of imaging and treatment requirements after first radiologic evidence of progression is provided in Table 24.
TABLE-US-00026 TABLE 26 Imaging and Treatment After First Radiologic Evidence of Progressive Disease Clinically Stable Clinically Unstable Imaging Treatment Imaging Treatment First radiologic Repeat imaging May continue study Repeat imaging Discontinue evidence of at 4 to 8 weeks intervention at the at 4 to 8 weeks treatment. progressive to confirm investigator's to confirm disease by progressive discretion while progressive RECIST 1.1 disease. awaiting confirmatory disease per tumor imaging by investigator's site by iRECIST. discretion only. Repeat tumor No additional Discontinue No additional Not applicable. imaging imaging treatment imaging required. confirms PD required. (exception is (iCPD) by possible upon iRECIST per consultation investigator with Sponsor). assessment. Repeat tumor Repeat imaging Continue study Repeat imaging Discontinue imaging shows at 4 to 8 weeks intervention at the at 4 to 8 weeks treatment. iUPD by to confirm investigator's to confirm iRECIST per progressive discretion. progressive investigator disease. May disease per assessment. occur at next investigator's regularly discretion only. scheduled imaging visit. Repeat tumor Continue Continue study Continue regularly May restart study imaging shows regularly intervention at the scheduled imaging intervention if iSD, iPR, or iCR scheduled investigator's assessments. condition has by iRECIST per imaging discretion improved and/or investigator assessments. clinically stable assessment. per investigator's discretion. Next tumor imaging should occur according to the regular imaging schedule.
Safety Assessment
[0742] Safety assessments include the collection of AEs and SAEs, monitoring of vital signs, physical examinations, performance of electrocardiograms (ECGs), a MUGA scan (using technetium-based tracer) or an ECHO at screening to assess LVEF), and pregnancy tests, among others.
Safety Endpoints
[0743] The safety endpoints include AEs, SAEs, and study intervention discontinuation due to AEs. In addition, safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, laboratory tests, and vital signs.
Adverse Event (AE)
[0744] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. [0745] NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
[0746] The following are included as AEs: [0747] Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the investigator. [0748] Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition. [0749] New conditions detected or diagnosed after study intervention administration even though it may have been present before the start of the study. [0750] Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. [0751] Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant medication. [0752] For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term should reflect the clinical symptoms or abnormal test result. An overdose without any associated clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or intentional overdose without adverse effect.”
[0753] The following events do not meet the AE definition for the purpose of this study: [0754] Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the AE. [0755] Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a hospital). [0756] Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen. [0757] Surgery planned prior to informed consent to treat a pre-existing condition that has not worsened.
Serious Adverse Event (SAE)
[0758] If an event is not an AE per the above, then it cannot be an SAE even if serious conditions are met. An SAE is defined as any untoward medical occurrence that, at any dose: [0759] Results in death. [0760] Is life-threatening. The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe. [0761] Requires inpatient hospitalization or prolongation of existing hospitalization. Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not an SAE. A pre-existing condition is a clinical condition that is diagnosed prior to the use of an MSD product and is documented in the participant's medical history. [0762] Results in persistent or significant disability/incapacity. The term disability means a substantial disruption of a person's ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial disruption. [0763] Is a congenital anomaly/birth defect. In offspring of participant taking the product regardless of time to diagnosis. [0764] Other important medical events. Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other situations such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. These events should usually be considered serious. Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.
Objective Response Rate (ORR)
[0765] The ORR is defined as the percentage of participants who achieve a confirmed CR or PR per RECIST 1.1 as assessed by BICR. Participants without follow-up scans will be considered nonresponders. ORR as assessed by investigator per RECIST 1.1 and iRECIST are considered exploratory endpoints.
Duration of Response (DOR)
[0766] For participants who demonstrate confirmed CR or PR per RECIST 1.1 as assessed by BICR, duration of response is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
Progression-free Survival (PFS)
[0767] Progression-free survival is defined as the time from date of randomization/allocation to the first documented progressive disease per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first.
Overall Survival (OS)
[0768] Overall survival is defined as the time from date of randomization/allocation to date of death from any cause.
[0769] The study treatments are outlined below in Table 27.
TABLE-US-00027 TABLE 27 Study Treatments Study Unit Regimen/ Treatment Dosage Dose Dose Dosage Route of Treatment Name Formulation Frequency Strengths Level(s) Administration Period MK-1308 Solution for Every 50 mg/ml 25 mg IV infusion Day 1 of each infusion 6 weeks 21-day cycle (Q6W) for up to 2 years of treatment Pembrolizu Solution for Every 400 mg IV infusion Day 1 of each mab infusion 6 weeks 21-day cycle (Q6W) for up to 2 years of treatment Lenvatinib Capsule Once Daily 10 mg 10, 14, Oral Daily on a 21- (QD) 4 mg or 20 day cycle for mg up to 2 years of treatment * 4 mg capsules provided for successive dose reduction of lenvatinib, if needed
TABLE-US-00028 TABLE 28 Investigational Summary Pembrolizumab + MK-1308 + Lenvatinib (SoA applicable to participants in the Safety Lead-In and Efficacy Phase) Study Posttreatment Period Treatment Cycle = 21 Days EOT.sup.b Safety Follow-Up Survival Notes Visit Timing / 1 2 Cycle 3 At 30 Q12W Q24W Q12W All procedures and assessments are to be Cycle Number and D/C Days performed prior to administration of study Onwards.sup.a After intervention unless otherwise indicated. Last Dose Cycle Day 1 8 15 1 8 15 1 Scheduling ±3 ±3 ±3 ±3 ±3 ±3 +7 ±7 ±7 ±7 Window (Days) Administrative Procedures Concomitant X X X X X X X X X X Concomitant medications will be recorded for Medication 90 days after last dose (or up to 120 days after Review last dose for SAEs). Randomization/ X Participants may be randomized/allocated up to Allocation 3 days prior to first dose of study intervention and after confirmation of eligibility. All procedures and assessments on first dose of study intervention should be performed after randomization/allocation. Dispensation of X X Day 1 of every cycle (eg. C1D1, C2D1, C3D1, Pembrolizumab etc.) Drug Kit Pembrolizumab X X Pembrolizumab will be administered Q6W (ie., Administration every other cycle) for up to 2 years of treatment. Dispensation of X X Day 1 of every cycle (eg. C1D1, C2D1, C3D1, MK-1308 drug etc.) kit MK-1308 X X MK-1308 will be administered Q6W (ie, every administration other cycle) for up to 2 years of treatment. Dispensation of X X X Day lof every cycle (eg., C1D1, C2D1, C3D1, Lenvatinib drug etc.) kit Note: Dose reductions of lenvatinib in the middle of a cycle will be allowed. Lenvatinib X X X X X X X Lenvatinib will be administered daily on a 21- Administration day cycle for up to 2 years of treatment. On C1D1, C2D1, C3D1, etc, lenvatinib will be taken 0-4 hours after completion of pembrolizumab and MK-1308 administration, if applicable. Lenvatinib will be taken in the clinic on CID 1, C3D1, C3D1, etc. Participants may be allowed to continue lenvatinib beyond 2 years, at the investigator’s discretion if there is clinical benefit. Subsequent X X X X All anticancer therapy will be recorded until Antineoplastic time of death or termination of survival follow- treatment up. If a clinic visit is not feasible, follow-up information may be obtained via telephone or email. .sup.aParticipants who attain an investigator-determined complete response (CR) and stop study intervention will have 30-day Safety Follow-up visit and move to the follow-up visits per SoA. .sup.bIf EOT visit occurs~30 days from last dose of study intervention, a 30-day Safety Follow-up visit is not required. In this situation, all procedures required at the 30-day Safety Follow-up visit and EOT are performed once and entered into the EOT visit only. End-of-treatment will be defined as the date when the participant discontinues all study interventions. .sup.cFor participants who D/C study intervention for reasons other than progressive disease, follow-up visits to monitor disease status continue until progressive disease or initiation of a new anticancer therapy. Participants who D/C study intervention due to progressive disease will proceed directly to Survival Follow-up. .sup.da brain MRI must be performed at screening for all participants. For participants with brain metastasis at screening, brain MRI should then be performed Q9W until Week 52 of study intervention and Q12W thereafter until Week 104; following Week 104, imaging should be performed every Q24W, or sooner if clinically indicated. Brain CT scan should only be used when MRI is contraindicated. The same imaging technique regarding modality and the use of contrast should be used in a participant throughout the study to optimize the visualization of existing and new tumor burden.
V. SEQUENCE LISTING
[0770] The present specification is being filed with a computer readable form (CRF) copy of the Sequence Listing. The CRF entitled 24797-WO-PCT-SEQLIST.txt, which was created on Feb. 18, 2021 and is 40.0 KB in size, is incorporated herein by reference in its entirety.
[0771] Table 29 below summarizes all sequences disclosed in the present specification.
TABLE-US-00029 TABLE 29 SEQ ID NOS and Corresponding Sequences SEQ ID NO Description Sequence 1 CDRH1 GFTFSDNW 2 CDRH2 IRNKPYNYET 3 CDRH3 TAQFAY 4 CDRL1 ENIYGG 5 CDRL2 GAT 6 CDRL3 QNVLRSPFT 7 CDRL3 QNVLSRHPG 8 CDRL3 QNVLSSRPG 9 VH 8D2/8D2 EVKLDETGGGLVQPGRPMKLSCVASGFTFSDNWMNW (RE) VRQSPEKGLEWLAQIRNKPYNYETYYSDSVKGRFTISR DDSKSSVYLQMNNLRGEDMGIYYCTAQFAYWGQGTL VTVSA 10 VL 8D2/8D2 DIQMTQSPASLSASVGETVTITCGTSENIYGGLNWYQRK (RE) QGKSPQLLIFGATNLADGMSSRFSGSGSGRQYSLKISSL HPDDVATYYCQNVLRSPFTFGSGTKLEI 11 VH 8D2H1L1 EVQLVESGGGLVQPGGSMRLSCAASGFTFSDNWMNW VRQAPGKGLEWLAQIRNKPYNYETYYSDSVKGRFTISR DDSKNSVYLQMNSLKTEDTGVYYCTAQFAYWGQGTL VTVSS 12 VL 8D2H1L1 DIQMTQSPSSLSASVGDRVTITCRTSENIYGGLNWYQRK QGKSPKLLIYGATNLASGMSSRFSGSGSGTDYTLKISSL HPDDVATYYCQNVLRSPFTFGSGTKLEIK 13 VH 8D2H2L2 EVQLVESGGGLVQPGGSMRLSCAASGFTFSDNWMNW VRQAPGKGLEWLAQIRNKPYNYETYYSASVKGRFTISR DDSKNSVYLQMNSLKTEDTGVYYCTAQFAYWGQGTL VTVSS 14 VL DIQMTQSPSSLSASVGDRVTITCRTSENIYGGLNWYQRK 8D2H2L2 and PGKSPKLLIYGATNLASGVSSRFSGSGSGTDYTLTISSLQ 8D2H2L2 PEDVATYYCQNVLRSPFTFGSGTKLEIK VARIANT 1 15 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSDNWMNWV 8D2H2L2 RQAPGKGLEWLAQIRNKPYNYETYYSASVKGRFTISRD VARIANT 1 DSKNSVYLQMNSLKTEDTGVYYCTAQFAYWGQGTLV TVSS 16 VH 8D2H3L3 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDNWMNWV RQAPGKGLEWVAQIRNKPYNYETEYAASVKGRFTISRD DSKNSAYLQMNSLKTEDTAVYYCTAQFAYWGQGTLV TVSS 17 VL 8D2H3L3 DIQMTQSPSSLSASVGDRVTITCRASENIYGGLNWYQQ KPGKAPKLLIYGATSLASGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQNVLRSPFTFGSGTKLEIK 18 VH8D2H2L15 EVQLVESGGGLVQPGGSMRLSCAASGFTFSDNWMNW VRQAPGKGLEWLAQIRNKPYNYETYYSASVKGRFTISR DDSKNSVYLQMNSLKTEDTGVYYCTAQFAYWGQGTL VTVSS 19 VL 8D2H2L15 DIQMTQSPSSLSASVGDRVTITCRTSENIYGGLNWYQRK PGKSPKLLIYGATNLASGVSSRFSGSGSGTDYTLTISSLQ PEDVATYYCQNVLSRHPGFGSGTKLEIK 20 VH8D2H2L17 EVQLVESGGGLVQPGGSMRLSCAASGFTFSDNWMNW VRQAPGKGLEWLAQIRNKPYNYETYYSASVKGRFTISR DDSKNSVYLQMNSLKTEDTGVYYCTAQFAYWGQGTL VTVSS 21 VL 8D2H2L17 DIQMTQSPSSLSASVGDRVTITCRTSENIYGGLNWYQRK PGKSPKLLIYGATNLASGVSSRFSGSGSGTDYTLTISSLQ PED VAT YYCQNVLS SRPGFGSGTKLEIK 22 Full Heavy EVQLVESGGGLVQPGGSLRLSCAASGFTFSDNWMNWV Chain RQAPGKGLEWLAQIRNKPYNYETYYSASVKGRFTISRD 8D2H2L2 DSKNSVYLQMNSLKTEDTGVYYCTAQFAYWGQGTLV VARIANT 1 TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK 23 Full Light DIQMTQSPSSLSASVGDRVTITCRTSENIYGGLNWYQRK Chain PGKSPKLLIYGATNLASGVSSRFSGSGSGTDYTLTISSLQ 8D2H2L2 PEDVATYYCQNVLRSPFTFGSGTKLEIKRTVAAPSVFIFP VARIANT 1 PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLS SP VTKSFNRGEC 24 CDRL1 RASQSVGSSYLA (Ipilimumab) 25 CDRL2 GAFSRAT (Ipilimumab) 26 CDRL3 QQYGSSPWT (Ipilimumab) 27 CDRH1 SYTMH (Ipilimumab) 28 CDRH2 FISYDGNNKYYADSVKG (Ipilimumab) 29 CDRH3 TGWLGPFDY (Ipilimumab) 30 Heavy chain QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWV VR RQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNS (Ipilimumab) KNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGT LVTVSS 31 Light chain VR EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQ (Ipilimumab) KPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRL E PEDFAVYYCQQYGSSPWTFGQGTKVEIK 32 Heavy Chain Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro (Ipilimumab) Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 33 Light Chain Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro (Ipilimumab) Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly He Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 34 Pembrolizumab, RASKGVSTSGYSYLH VL-CDRI 35 Pembrolizumab, LASYLES VL-CDR2 36 Pembrolizumab, QHSRDLPLT VL-CDR3 37 Pembrolizumab, EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHW VL YQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTI SSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 38 Pembrolizumab, EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHW lightchain YQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTI SSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC 39 Pembrolizumab, NYYMY VH-CDR1 40 Pembrolizumab, GINPSNGGTNFNEKFKN VH-CDR2 41 Pembrolizumab, RDYRFDMGFDY VH-CDR3 42 Pembrolizumab, QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYW VH VRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTD SSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYW GQGTTVTVSS 43 Pembrolizumab, QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYW heavychain VRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTD SSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYW GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK